Data on the effects of omega-3 fatty acids (n-3 FA) on cardiovascular risk are inconsistent. Some observational studies and randomized trials have suggested that n-3 FA may lower the risk of sudden cardiac death (SCD) and coronary events, possibly through antiarrhythmic effects. In contrast, other studies have reported that n-3 FA reduce the risk of nonfatal coronary events but not fatal events or SCD. Although animal studies have consistently demonstrated antiarrhythmic effects of n-3 FA, only one of the 3 randomized clinical trials specifically designed to evaluate antiarrhythmic effects of n-3 FA supplements among patients with implantable cardioverter defibrillators showed antiarrhythmic properties of n-3 FA supplements. In addition, a recent meta-analysis of other randomized trials showed no clear benefit of either long-chain or short-chain n-3 FA on the risk of cardiovascular disease and all-cause mortality. While a higher correlation between n-3 FA in red blood cell (RBC) and cardiac cell membranes has been reported, limited studies have used this novel technique to assess the effects of n-3 FA on coronary artery disease (CAD) death, cardiovascular (CVD) death, or myocardial infarction (MI). Given the current inconsistencies, additional studies of n-3 FA on CAD are needed as recommended by the 2005 workshop on n-3 FA. Since short-chain FA can be converted into long-chain FA in vivo and many familiar food products can be enriched with short-chain FA, an intervention trial based on such enriched foods might have a better long-term compliance than a supplement trial. The current application will use a prospective, nested, case-control design to examine whether or not short-chain and long-chain n-3 FA from RBC membranes and from the diet are associated with a lower risk of fatal CAD, CVD death, and MI in the Physicians'Health Study (PHS). This project will test the following hypotheses: (i) higher levels of RBC long- and short-chain n-3 FA are associated with a lower risk of fatal CAD, CVD death, and MI;(ii) higher levels of RBC n-3 FA are positively correlated with dietary n-3 FA;(iii) contrary to RBC n-3 FA, higher levels of dietary n-3 FA are modestly associated with a lower risk of fatal CAD, CVD death, and MI. The primary aim is to examine the association between RBC long-chain n-3 FA on the risk of fatal CAD, CVD death, and MI. The secondary aim will assess the effects of RBC short-chain and dietary n-3 FA on the risk of fatal CAD, CVD death, and MI;and the correlation between dietary and RBC n-3 FA. Several features of the PHS make it an excellent and cost-effective resource to answer these important questions: 1) frozen red blood cells were collected among 17,469 men at baseline;2) data on mortality and coronary endpoints are systematically collected and validated;3) we have collected data on key covariates including dietary factors, to control for major confounding factors. The proposed study will increase our understanding on the role of n-3 FA on CAD and will provide pilot data to support a future application seeking funding for a larger primary prevention trial to investigate beneficial effects of n-3 enriched foods on CAD. The results of this study may help identify which n-3 FA could be used to enrich foods and may lead to significant improvement in primary prevention of CAD, which is a public health imperative. PUBLIC HEALTH RELEVANCE: Heart attack is one of the leading causes of deaths in the US. The current project will examine whether omega-3 fatty acids - a type of polyunsaturated fats found mostly in fatty fish, flaxseed or canola oils - can lower the risk of fatal coronary events, cardiovascular death, or heart attack among US male physicians who participated in a trial of vitamin supplements. Findings of this study may provide important information that could shape dietary recommendations to prevent coronary events.